Type II (or Type 2) diabetes mellitus (non-insulin-dependent diabetes mellitus or NIDDM) is a metabolic disorder involving dysregulation of glucose metabolism and insulin resistance, and long-term complications involving the eyes, kidneys, nerves, and blood vessels. Type II diabetes mellitus usually develops in adulthood (middle life or later), although it is increasingly reported in adolescents. It is described as the body""s inability to make either sufficient insulin (abnormal insulin secretion) or its inability to effectively use insulin (resistance to insulin action in target organs and tissues). More particularly, patients suffering from Type II diabetes mellitus have a relative insulin deficiency. That is, in these patients, plasma insulin levels are normal to high in absolute terms, although they are lower than predicted for the level of plasma glucose that is present.
Type II diabetes mellitus is characterized by the following clinical signs or symptoms: persistently elevated plasma glucose concentration or hyperglycemia; polyuria; polydipsia and/or polyphagia; chronic microvascular complications such as retinopathy, nephropathy and neuropathy; and macrovascular complications such as hyperlipidemia and hypertension. These micro-and macro-vascular complications can lead to blindness, end-stage renal disease, limb amputation and myocardial infarction.
Syndrome X, is also termed Insulin Resistance Syndrome (IRS), Metabolic Syndrome, or Metabolic Syndrome X. It is a disorder that presents risk factors for the development of Type II diabetes mellitus and cardiovascular disease including glucose intolerance, hyperinsulinemia and insulin resistance, dyslipidemia (eg, high triglycerides and low HDL-cholesterol), hypertension and obesity.
Typical treatment of Type II diabetes mellitus and Syndrome X focuses on maintaining the blood glucose level as near to normal as possible and includes diet and exercise, and when necessary, treatment with anti-diabetic agents, insulin or a combination thereof. TYPE II diabetes that cannot be controlled by dietary management is treated with oral anti-diabetic agents including, but not limited to, sulfonylureas (e.g., not limited to first generation: chlorpropamide, tolazamide, tolbutamide; second generation: glyburide, glipizide; and third generation: glimepiride), biguanides (e.g., metformin), thiazolidinediones (e.g., rosiglitazone, pioglitazone, troglitazone), alpha-glucosidase inhibitors (e.g., acarbose, miglitol), meglitinides (e.g., repaglinide), other insulin-sensitizing compounds, and/or other anti-obesity agents (e.g., orlistat or sibutramine). For Syndrome X, the anti-diabetic agents are additionally combined with pharmacological agents for the treatment of the concomitant co-morbidities (e.g., antihypertensives for hypertension, hypolipidemic agents for hyperlipidemia).
First-line therapies typically include metformin and sulfonylureas as well as thiazolidinediones. Metformin monotherapy is a first line choice, particularly for treating Type II diabetic patients who are also obese and/or dyslipidemic. Lack of an appropriate response to metformin is often followed by treatment with metformin in combination with sulfonylureas, thiazolidinediones, or insulin. Sulfonylurea monotherapy (including all generations of drugs) is also a common first line option. Another first line therapy choice may be thiazolidinediones. Patients who do not respond appropriately to oral anti-diabetic monotherapy, are given combinations of these agents. When glycemic control cannot be maintained with oral antidiabetics alone, insulin therapy is used either as a monotherapy, or in combination with oral antidiabetic agents. These same strategies, optionally in combination with additional strategies (e.g., anti-hypertensive) can be used for the treatment of Syndrome X.
Anti-diabetic agents include, but are not limited to:
(a) Sulfonylureas, which increase insulin production by stimulating pancreatic beta cells, and therefore act as insulin secretagogues. The primary mechanism of action of sulfonylureas is to close ATP-sensitive potassium channels in the beta-cell plasma membrane, initiating a chain of events that result in insulin release. Suitable examples of sulfonylureas include, but are not limited to chlorpropamide, tolazamide, tolbutamide, glyburide, glipizide, glimepiride, and like.
(b) Meglitinides, another class of insulin secretagogues, that have a mechanism of action distinct from that of the sulfonylureas. Suitable examples of meglitinides include, but are not limited to repaglinide.
(c) Agents which modify insulin secretion such as Glucagon-like Peptide-1(GLP-1) and it""s mimetics, Glucose-insulinotropic peptide (GIP) and it""s mimetics, Exendin and it""s mimetics, and Dipeptyl Protease Inhibitors (DPPIV).
(d) Biguanides which decrease liver glucose production and increase the uptake of glucose. Suitable examples include, but are not limited to metformin.
(e) Thiazolidinediones, insulin sensitizing drugs which decrease peripheral insulin resistance by enhancing the effects of insulin at target organs and tissues. These drugs bind and activate the nuclear receptor, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) which increases transcription of specific insulin-responsive genes. Suitable examples of PPAR-gamma agonists are the thiazolidinediones which include, but are not limited to rosiglitazone, pioglitazone, troglitazone, isaglitazone (known as MCC-555), 2-[2-[(2R)-4-hexyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl]ethoxy]-benzene acetic acid, and the like. Additionally, the non-thiazolidinediones also act as insulin sensitizing drugs, and include, but are not limited to GW2570, and the like.
(f) Retinoid-X receptor (RXR) modulators, also insulin sensitizing drugs, which include, but are not limited to targretin, 9-cis-retinoic acid, and the like.
(g) Other insulin sensitizing agents include, but are not limited to INS-1, PTP-1B inhibitors, GSK3 inhibitors, glycogen phosphorylase a inhibitors, fructose-1,6-bisphosphatase inhibitors, and the like.
(h) Alpha-glucosidase inhibitors which act to inhibit alpha-glucosidase. Alpha-glucosidase converts fructose to glucose, thus these inhibitors delay the digestion of carbohydrates. The undigested carbohydrates are subsequently broken down in the gut, thereby reducing the post-prandial glucose peak. Suitable examples include, but are not limited to, acarbose and miglitol.
(i) Insulins, including regular or short-acting, intermediate-acting, and long-acting insulins, inhaled insulin and insulin analogues such as insulin molecules with minor differences in the natural amino acid sequence. These modified insulins may have faster onset of action and/or shorter duration of action.
(j) Small molecule mimics of insulin, including, but not limited to L-783281, TE-17411, and the like.
(k) Na-glucose co-transporter inhibitors which inhibit the renal reabsorption of glucose such as T-1095, T-1095A, phlorizen, and the like.
(l) Amylin agonists which include, but are not limited to pramlintide, and the like.
(k) Glucagon antagonists such as AY-279955, and the like.
In addition to antidiabetic agents, therapies may include add-on treatment with anti-obesity agents such as orlistat, a pancreatic lipase inhibitor, which prevents the breakdown and absorption of fat; or sibutramine, an appetite suppressant and inhibitor of the reuptake of serotonin, norepinephrine and dopamine in the brain. Other potential add-on anti-obesity agents include, but are not limited to, appetite-suppressants acting through adrenergic mechanisms such as benzphetamine, phenmetrazine, phentermine, diethylpropion, mazindol, sibutramine, phenylpropanolamine or, ephedrine; appetite-suppressant agents acting through serotonergic mechanisms such as quipazine, fluoxetine, sertraline, fenfluramine, or dexfenfluramine; appetite-suppressant agents acting through dopamine mechanisms, eg, apomorphine; appetite-suppressant agents acting through histaminergic mechanisms (eg, histamine mimetics, H3 receptor modulators); enhancers of energy expenditure such as beta-3 adrenergic agonists and stimulators of uncoupling protein function; leptin and leptin mimetics; neuropeptide Y antagonists; melanocortin-1, 3 and 4 receptor modulators; cholecystokinin agonists; glucagon-like peptide-1 (GLP-1) mimetics and analogues (eg, Exendin); androgens (eg, dehydroepiandrosterone and derivatives such as etiocholandione), testosterone, anabolic steroids (eg, oxandrolone), and steroidal hormones; galanin receptor antagonists; cytokine agents such as ciliary neurotrophic factor; amylase inhibitors; enterostatin agonists/mimetics; orexin/hypocretin antagonists; urocortin antagonists; bombesin agonists; modulators of protein kinase A; corticotropin-releasing factor mimetics; cocaine- and amphetamine-regulated transcript mimetics; calcitonin-gene related peptide mimetics; and fatty acid synthase inhibitors.
Add-on therapy using Compounds of Formula I: 
has not, however, yet been contemplated in the art.
Such compounds are structurally novel antiepileptic compounds that are highly effective anticonvulsants in animal tests (MARYANOFF, B. E, NORTEY, S. O., GARDOCKI, J. F., SHANK, R. P. AND DODGSON, S. P. J. Med. Chem. 1987, 30, 880-887; MARYANOFF, B. E., COSTANZO, M. J., SHANK, R. P., SCHUPSKY, J. J., ORTEGON, M. E., AND VAUGHT J. L. Bioorg. Med. Chem. Lett. 1993, 3, 2653-2656; SHANK, R. P., GARDOCKI, J. F., VAUGHT, J. L., DAVIS, C. B., SCHUPSKY, J. J., RAFFA, R. B., DODGSON, S. J., NORTEY, S. O., MARYANOFF, B. E. Epilepsia 1994, 35, 450-460; MARYANOFF B E, COSTANZO M J, NORTEY S O, GRECO M N, SHANK R P, SCHUPSKY J J, ORTEGON M P, VAUGHT J L. J. Med. Chem. 1998, 41, 1315-1343). These compounds are covered by three U.S. Pat. No. 4,513,006, No. 5,242,942, and No. 5,384,327. One of these compounds 2,3:4,5-bis-O-(1-methylethylidene)-xcex2-D-fructopyranose sulfamate known as topiramate has been demonstrated in clinical trials of human epilepsy to be effective as adjunctive therapy or as monotherapy in treating simple and complex partial seizures and secondarily generalized seizures (E. FAUGHT, B. J. WILDER, R. E. RAMSEY, R. A. REIFE, L D. KRAMER, G. W. PLEDGER, R. M. KARIM et. al., Epilepsia 1995, 36 (S4), 33; S. K. SACHDEO, R. C. SACHDEO, R. A. REIFE, P. LIM and G. PLEDGER, Epilepsia 1995, 36 (S4), 33; T. A. GLAUSER, Epilepsia 1999, 40 (S5), S71-80; R. C. SACHDEO, Clin. Pharmacokinet. 1998, 34, 335-346), and is currently marketed for the treatment of seizures in patients with simple and complex partial epilepsy and seizures in patients with primary or secondary generalized seizures in the United States, Europe and most other markets throughout the world. Despite the fact that topiramate, having the brand name Topomax(copyright) is widely marketed it has not been used on an add-on therapy with anti-diabetic agents for treating Type II Diabetes Mellitus or Syndrome X.
Compounds of Formula I were initially found to possess anticonvulsant activity in the traditional maximal electroshock seizure (MES) test in mice (SHANK, R. P., GARDOCKI, J. F., VAUGHT, J. L., DAVIS, C. B., SCHUPSKY, J. J., RAFFA, R. B., DODGSON, S. J., NORTEY, S. O., and MARYANOFF, B. E., Epilepsia 1994, 35, 450-460). Subsequent studies revealed that Compounds of Formula I were also highly effective in the MES test in rats. Topiramate was also found to effectively block seizures in several rodent models of epilepsy (J. NAKAMURA, S. TAMURA, T. KANDA, A. ISHII, K. ISHIHARA, T. SERIKAWA, J. YAMADA, and M. SASA, Eur. J. Pharmacol. 1994, 254, 83-89), and in an animal model of kindled epilepsy (A. WAUQUIER and S. ZHOU, Epilepsy Res. 1996, 24, 73-77).
More recently compounds of formula I have been found to be effective for maintaining weight loss and in the treatment of obesity, as disclosed in U.S. Pat. No. 6,071,537 (WO 9800130). Thakur et al in WO9944581 disclose the use of topiramate for the treatment of diabetes.
It has now been found that compounds of the following formula (I): 
wherein X is O or CH2, and R1, R2, R3, R4 and R5 are as defined herein when administered in combination with one or more anti-diabetic agents, as defined herein, are useful in the treatment of Type II Diabetes Mellitus and Syndrome X.
The sulfamates of the invention are of the following formula (I): 
wherein
X is CH2 or oxygen;
R1 is hydrogen or alkyl; and
R2, R3, R4 and R5 are independently hydrogen or lower alkyl and, when X is CH2, R4 and R5 may be alkene groups joined to form a benzene ring and, when X is oxygen, R2 and R3 and/or R4 and R5 together may be a methylenedioxy group of the following formula (II): 
wherein
R6 and R7 are the same or different and are hydrogen, lower alkyl or are alkyl and are joined to form a cyclopentyl or cyclohexyl ring.
R1 in particular is hydrogen or alkyl of about 1 to 4 carbons, such as methyl, ethyl and iso-propyl. Alkyl throughout this specification includes straight and branched chain alkyl. Alkyl groups for R2, R3, R4, R5, R6 and R7 are of about 1 to 3 carbons and include methyl, ethyl, iso-propyl and n-propyl. When X is CH2, R4 and R5 may combine to form a benzene ring fused to the 6-membered X-containing ring, i.e., R4 and R5 are defined by the alkatrienyl group xe2x95x90Cxe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90.
A particular group of compounds of formula (I) is that wherein X is oxygen and both R2 and R3 and R4 and R5 together are methylenedioxy groups of the formula (II), wherein R6 and R7 are both hydrogen both alkyl or combine to form a spiro cyclopentyl or cyclohexyl ring, in particular where R6 and R7 are both alkyl such as methyl. A second group of compounds is that wherein X is CH2 and R4 and R5 are joined to form a benzene ring. A third group of compounds of formula (I) is that wherein both R2 and R3 are hydrogen.
The compounds of formula (I) may be synthesized by the following methods:
(a) Reaction of an alcohol of the formula RCH2OH with a chlorosulfamate of the formula ClSO2NH2 or ClSO2NHR1 in the presence of a base such as potassium t-butoxide or sodium hydride at a temperature of about xe2x88x9220xc2x0 to 25xc2x0 C. and in a solvent such as toluene, THF, or dimethylformamide wherein R is a moiety of the following formula (III): 
(b) Reaction of an alcohol of the formula RCH2OH with sulfurylchloride of the formula SO2Cl2 in the presence of a base such as triethylamine or pyridine at a temperature of about xe2x88x9240xc2x0 to 25xc2x0 C. in a solvent such as diethyl ether or methylene chloride to produce a chlorosulfate of the formula RCH2OSO2Cl.
The chlorosulfate of the formula RCH2OSO2Cl may then be reacted with an amine of the formula R1NH2 at a temperature of abut 40xc2x0 to 25xc2x0 C. in a solvent such as methylene chloride or acetonitrile to produce a compound of formula (I). The reaction conditions for (b) are also described by T. Tsuchiya et al. in Tetrahedron Lett., 1978, 3365.
(c) Reaction of the chlorosulfate RCH2OSO2Cl with a metal azide such as sodium azide in a solvent such as methylene chloride or acetonitrile yields an azidosulfate of the formula RCH2OSO2N3 as described by M. Hedayatullah in Tetrahedron Lett. 1975, 2455. The azidosulfate is then reduced to a compound of formula (I) wherein R1 is hydrogen by catalytic hydrogenation, e.g. with a noble metal and H2 or by heating with copper metal in a solvent such as methanol.
The starting materials of the formula RCH2OH may be obtained commercially or as known in the art. For example, starting materials of the formula RCH2OH wherein both R2 and R3 and R4 and R5 are identical and are of the formula (II) may be obtained by the method of R. F. Brady in Carbohydr. Res. 1970, 14, 35 or by reaction of the trimethylsilyl enol ether of a R6COR7 ketone or aldehyde with fructose at a temperature of about 25xc2x0 C., in a solvent such a halocarbon, e.g. methylene chloride in the presence of a protic acid such as hydrochloric acid or a Lewis Acid such as zinc chloride. The trimethylsilyl enol ether reaction is described by G. L. Larson et al. in J. Org. Chem. 1973, 38, 3935.
Further, carboxylic acids and aldehydes of the formulae RCOOH and RCHO may be reduced to compounds of the formula RCH2OH by standard reduction techniques, e.g. reaction with lithium aluminum hydride, sodium borohydride or borane-THF complex in an inert solvent such a diglyme, THF or toluene at a temperature of about 0xc2x0 to 100xc2x0 C., e.g. as described by H. O. House in xe2x80x9cModern Synthetic Reactionsxe2x80x9d, 2nd Ed., pages 45 to 144 (1972).
The compounds of formula I may also be made by the process disclosed U.S. Pat. No. 4,513,006, No. 5,242,942, and No. 5,384,327, which are incorporated by reference herein.
The compounds of formula I include the various individual isomers as well as the racemates thereof, e.g., the various alpha and beta attachments, i.e., below and above the plane of the drawing, of R2, R3, R4 and R5 on the 6-membered ring. Preferably, the oxygen of the methylenedioxy group (II) are attached on the same side of the 6-membered ring.
Anti-diabetic agents useful for the treatment of Type II diabetes mellitus and Syndrome X include, but are not limited to, sulfonylureas, meglitinides, agents which modify insulin secretion, biguanides, thiazolidinediones, PPAR-gamma agonists, Retinoid-X receptor (RXR) modulators, insulin sensitizing agents, alpha-glucosidase inhibitors, insulins, small molecule mimics of insulin, Na-glucose co-transporter inhibitors, amylin agonists, glucagon antagonists, and the like.
Suitable examples of anti-diabetic agents include, chlorpropamide, tolazamide, tolbutamide, glyburide, glipizide, glimepiride, repaglinide, metformin, rosiglitazone, pioglitazone, troglitazone, isaglitazone (known as MCC-555), 2-[2-[(2R)-4-hexyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl]ethoxy]-benzene acetic acid, GW2570, targretin, 9-cis-retinoic acid, ascarbose, miglitol, L-783281, TE-17411, T-1095, BAY-279955, phlorizen, pramlintide, regular-acting insulin, short-acting insulin, intermediate-acting insulin, long-acting insulin, inhaled insulin, insulin analogues, acetohexamide, buformin, glibornuride, glyhexamide, glymidine, linogliride, palmoxirate, zopolrestat; etoformin, gllicalzide, glypinamide, and the like.
In addition to antidiabetic agents, add-on therapeutic agents may include anti-obesity agents such as orlistat, sibutramine, mazindol, benzphetamine, phenmetrazine, phentermine, diethylpropion, mazindol, sibutramine, phenylpropanolamine, ephedrine, quipazine, fluoxetine, sertraline, fenfluramine, dexfenfluramine, apomorphine, Exendin, dehydroepiandrosterone, etiocholandione, testosterone, oxandrolone, and the like. In addition, therapies may also include add-on treatment with anti-hypertensive agents and/or hypolipidemic agents.
As used herein, the terms xe2x80x9cSyndrome Xxe2x80x9d, xe2x80x9cMetabolic Syndromexe2x80x9d and xe2x80x9cMetabolic Syndrome Xxe2x80x9d shall mean a disorder that presents risk factors for the development of Type II diabetes mellitus and cardiovascular disease and is characterized by insulin resistance and hyperinsulinemia and may be accompanied by one or more of the following: (a) glucose intolerance, (b)Type II diabetes, (c)dyslipidemia, (d) hypertension and (e) obesity.
The ability of the compounds of formula I administered in combination with an anti-diabetic agent to treat Type II diabetes mellitus and Syndrome X is based on the following case studies.